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Although dementia with Lewy bodies (DLB) is the second-most-common cause of dementia, research into the underlying pathophysiology lags behind Alzheimer’s and Parkinson’s disease. Guerreiro and colleagues recently conducted the first large-scale genome-wide association study and identified three previously known associations: apolipoprotein E (ApoE), α-synuclein (SCNA), and glucocerebrosidase (GBA). In addition, a novel locus was found in discovery and validation assays—CNTN1, a glycosylphophotidyl inositol-anchored neuronal membrane protein that may serve as a cell-adhesion molecule. Even more interesting, the CNTN1 locus is located near the Lrrk2 locus, which has been linked to Parkinson’s disease. While additional GWAS studies are needed, with this new knowledge it may be possible to design experimental paradigms to ultimately model DLB pathophysiology and develop DLB-specific targets for new therapeutic interventions.

The recently published Fourth Report of the DLB Consortium, which updated recommendations about DLB diagnosis and management, prioritized “strategies to progress critical areas of biological research, include collecting samples from large population-based cohorts, and developing a publically available DLB genetic database and a repository for DLB exome data” (July 2017 news). Drs. Guerreiro, Bras, and colleagues should be congratulated on progressing this agenda by publishing the first genome-wide association study of DLB, which confirms previously reported associations with ApoE, SNCA, and GBA and suggests other novel loci, namely CNTN1.

We now know from their work that the heritable component of DLB is approximately 36 percent, similar to both AD and PD, and although the three disorders may share common genes, the specific mutations or combinations of them appear to differ. DLB families will of course ask whether they should now come forward for clinical genetic testing and risk profiling, but it is still too early to advocate this. New and larger samples are required to continue the search/validation for other DLB genes. Although the gold standard will always be pathologically verified cases, my view is that since clinical diagnostic criteria for DLB, properly applied, have greater than 90 percent positive predictive accuracy, the goal can be achieved using well-characterized clinical cases. As the DLB4 report concluded, “In order to best advance DLB research, global harmonization efforts are required to create networks of researchers and research participants that share common platforms for data and biomarker collection, outcome measures for clinical-translational research, and shared terminology across language, cultures, and traditions.”